Project Summary: Cancer cell metabolism comprises of a number of aberrantly regulated metabolic pathways including lipid synthesis (lipogenesis), glycolysis (the Warburg Effect). While prostate cancer PCa) cells do not exhibit elevated glucose uptake, a characteristic of the Warburg effect, they do feature elevated glycolysis and lipogenesis enzyme expression. Also whereas normal cells obtain lipids primarily from exogenous sources PCa cells depend on de novo lipid synthesis. Importantly, elevated glycolysis and lipogenesis enzyme expression drive metabolite production for nucleotide, protein and lipid production, which facilitate cell proliferation, energy production, intracellular signaling and immune evasion. Importantly lipogenesis and aberrant glycolysis enzyme expression have been identified, as bona-fide mediators of PCa etiology and invasiveness, therefore targeted disruption of these pathways are a potential treatment approach for PCa. A number of inhibitors have been developed to target cancer metabolism. Unfortunately these inhibitors have poor efficacy and have associated toxic side effects including severe weight-loss and anorexia in rodent cancer models. As a result there are currently no treatments for PCa that target oncogenic metabolism currently used in the clinic. PCa treatments that focus on blocking androgen receptor activity and cell division have not been able to extend patient lifespan substantially. This is due to PCa cells adapting and continuing to grow and invade other tissues by ?rewiring? androgen receptor signaling and bypassing targeted cellular pathways. Metastatic, castration resistant PCa is responsible for all PCa deaths. Therefore our objective is to develop a cancer metabolism inhibitor that is effective, safe and will be able to replace, supplement or enhance current treatments. We hypothesized that suppression of the transcriptional activity of the liver-X-receptor (LXR); a master regulator of expression of multiple glycolysis and lipogenesis genes could be a potent means of inhibiting cancer metabolism. Therefore we designed a LXR inverse agonist: SR9243 that suppresses LXR transcriptional activity. SR9243 significantly blocks the Warburg effect and lipogenesis and is able to disrupt PCa cell growth without producing weight loss or other undesired side effects. To investigate whether LXR inverse agonism, using SR9243, is a useful treatment approach for PCa we will address 2 specific aims. Specific Aim 1 will test the efficacy of SR9243 against PCa tumors in a PCa orthotopic primary tumor model and a metastatic model. Specific Aim 2 will investigate whether SR9243 is able to enhance the efficacy of currently used PCa treatments when used in combination using a patient derived xenograft model of PCa. This study should generate a novel treatment approach for PCa and will lay the foundation for future projects aimed at exploring the mechanistic role of LXR transcriptional activity in PCa metabolism.